Long term objective: To determine the safety and efficacy of endurance exercise training as therapy and the potentially adverse effects of habitual physical inactivity in patients with skeletal muscle mitochondrial electron transport chain defects due to heteroplasmic mitochondrial DNA mutations. Specific Aims: 1) To establish that in patients with mtDNA defects, endurance training induces mitochondrial proliferation whereby increases in wild-type mtDNA levels offset high levels of mutant mtDNA in individual muscle cells, thereby improving mitochondrial oxidative capacity and ultimately exercise performance and quality of life;and to determine effects of endurance training on cardiac function and capillary formation in skeletal muscle;2) In these patients, to establish the effects of prolonged physical inactivity (normally associated with down- regulation of mitochondrial volume) on levels of mutant mtDNA and oxidative capacity in muscle and upon cardiac function and capillary levels in skeletal muscle. Research Design: Patients will undergo physiological exercise testing, cardiac evaluation and muscle needle biopsy and then be randomized to regular exercise training or no training for 6 months with retesting at the end of that time;then untrained patients will train and trained patients detrain for 6 months with repeat testing at the end of that time;thereafter, patients will be encouraged to train for an additional 1 year with retesting at the end of that period. Training and detraining effects on mitochondrial genotype and function will be determined by changes in copy number of mutant and wild-type mtDNA;these genetic changes will be correlated with respiratory complex enzymatic activity and assembly in individual muscle cells or homogenate. Training effects on muscle and cardiovascular function will be assessed by monitoring peak work, oxygen utilization, cardiac output and stroke volume in cycle exercise, and by monitors of quality of life. Given the prevalence of mitochondrial myopathies attributable to mitochondrial DNA mutations, the current lack of any effect therapy, and the possible negative effects of physical inactivity on muscle oxidative capacity, there is an immediate need to define appropriate recommendations for exercise training in patients with mitochondrial electron transport chain defects.